The long-term objectives of this proposal include determining whether human butyrylcholine-esterase (BChE) might be of use in the treatment of cocaine-induced toxicity and abuse and to compare the effects of BChE with those of a more active mutant BChE. BChE will be purified from human blood by Dr. Lockridge at the University of Nebraska Medical Center. Dr. Lockridge will also purify a mutant of human BChE (A328W) as it is secreted by cultured cells. Then, at the University if Michigan, rhesus monkeys will be studied for their response to human BChE under three circumstances that involve cocaine administration. The ability of the BChEs 1) to modify the effects of cocaine on food-reinforced behavior; 2) to modify the reinforcing effects of cocaine; and 3) to alter the cardiovascular effects of cocaine will be studied in these animals. The dose-related effects of the BChEs will be studied extensively, as will the ability of repeated administration of effective doses of the BChEs to continue to modify the behavioral and cardiovascular effects of a range of doses of cocaine. In addition, particular attention will be paid to the duration of the effect of different doses of human BChE. The possibility that human BChE can eventually be used as a safe and effective treatment of cocaine abuse and toxicity is being explored through these studies.